Diabetes is a group of endocrine-metabolic diseases having a common marker of high blood sugar. Metabolic disorders of sugar, protein, fat and secondary water, and electrolyte are caused by absolute or relative insufficiency of insulin secretion. Diabetes can involve chronic damage and dysfunction of various systems throughout the body, especially eye, kidney, heart, blood vessel and nerves, and even induce a number of fatal complications. With the aging of the world's population, diabetes that seriously endangers human health has become a common and frequently-occurring disease. Research data shows that the number of diabetic patients worldwide has increased from 150 million in 2000 to 280 million. It is estimated that there will be nearly 500 million diabetic patients worldwide by 2030.
Glucose transporter regulates and controls the balance of glucose metabolism in the normal state of human. Sodium-glucose cotransporter (SGLT) is a known glucose transporter. SGLT includes SGLT1 and SGLT2. SGLT1 is expressed in small intestine and the distal S3 segment of renal proximal convoluted tubules, and absorbs about 10% of the sugar. SGLT2 is mainly expressed in the proximal SI segment of renal proximal convoluted tubules, and is responsible for more than 90% glucose reabsorption.
Therefore, inhibition of SGLT, particularly SGLT2, can inhibit the reabsorption of sugar, thereby allowing the sugar to be excreted in the urine and lowering the concentration of sugar in the blood.
Dapagliflozin, developed by Bristol-Myers Squibb and AstraZeneca, is used for the treatment of type II diabetes (a sodium-glucose cotransporter-2 (SGLT-2) inhibitor).
Bristol-Myers Squibb and AstraZeneca submitted an application to the European Medicines Agency (EMA) in December 2010, and the European committee for medicinal products for human use recommended the approval of dapagliflozin for the treatment of type II diabetes in April 2012.
Bristol-Myers Squibb and AstraZeneca also submitted an NDA application to the Food and Drug Administration (FDA) in December 2010. The FDA issued a response letter requesting an increase in clinical data in January 2012.
The chemical name of dapagliflozin is 2-chloro-5-(β-D-glucopyranosyl-1-yl)-4′-ethoxydiphenylmethane, and the chemical structure is as follows:

In general, for the purpose of the operability of the preparation of drug substance and formulation, the stability of the drug preservation, and improving the efficacy of the drug, it is necessary to make the drug into a crystalline state.
By far, regarding the report on crystal forms of dapagliflozin, only the original crystal form patent (CN101479287) has reported 9 crystal forms: dapagliflozin solvates and complexes of dapagliflozin and amino acids. Details are as follows:
CrystalCrystal formformdescriptionPreparation method of crystal formIaDapagliflozinIn a system of (S)-propylene glycol,(S)-propylenewater and dapagliflozin, cyclohexaneglycoland methyl tert-butyl ether were added,monohydrateand the mixture was cooled to 5° C.,then stirred to precipitate a crystal.IbDapagliflozinIn a system of (R)-propylene glycol,(R)-propylenewater and dapagliflozin, cyclohexaneglycoland methyl tert-butyl ether were added,monohydrateand the mixture was cooled to 5° C.,then stirred to precipitate a crystal.IcDapagliflozinDapagliflozin was dissolved in ethanol,ethanol dihydrateand the mixture was diluted with waterand cooled to −10 to −20° C., and thenstirred to precipitate a crystal.IdDapagliflozinDapagliflozin was dissolved in ethyleneethylene glycolglycol aqueous solution, and crystal Iadihydratewas added, and then stirred to precipitatea crystal.IeDapagliflozinDapagliflozin was dissolved in ethyleneethylene glycolglycol aqueous solution, and crystal Icdihydratewas added, and then stirred to precipitatea crystal.IhDapagliflozin-L-proline was dissolved in water underdi-L-prolineheating. Isopropanol and a solution ofcomplexdapagliflozin in isopropanol were addedsuccessively to precipitate a crystal.IiDapagliflozin-L-proline was dissolved in 90% ethanol/L-prolinewater under heating. A solution ofcomplexdapagliflozin in ethanol was added, andthen the mixture was cooled to −20° C.to precipitate a crystal.IjDapagliflozin-L-proline and dapagliflozin were dissolvedL-prolinein 97% ethanol/water under heating. Thesemihydratemixture was cooled to −20° C. beforeadding crystal Ii, and then stirred toobtain a white solid Ij in the form of acomplex.IkDapagliflozin-L-phenylalanine was dissolved in waterL-phenylalanineunder heating, and then added to a solutioncomplexof dapagliflozin in ethanol to obtain thecomplex Ik.
It is well known that, when a drug crystal exists in the form of a solvate or a complex, in addition to the active ingredient (i.e., API) having a therapeutic effect in the drug substances, there are some substances which are not related to the therapeutic effect of the drug, and are often harmful to the human body. In the formula study of formulations, as for a drug in the form of solvates or complexes, due to the presence of non-API components, the compatibility of drug substances and auxiliary materials, the ratio of drug substances and auxiliary materials, and the weight of the formulations are often affected. Therefore, the drug crystal form which is generally present in the form of a solvate or a complex is not suitable for the development of pharmaceutical preparations.
In addition, the patent application WO2013079501A disclosed crystal forms A and B of dapagliflozin hydrate. WO2015117538A and CN104829573A disclosed a new crystal form of dapagliflozin, respectively. These crystal forms disclosed in the above patent applications are not crystal forms of solvates. However, it is found that the melting points of the above crystal forms are too low, less than 35° C. by the DSC melting point test. During the tableting process, the local temperature was too high, thereby causing the active material to melt, which is not conducive to drug production.